This proposal is focused on the physiological functions of Protein Kinase A (PKA) in the regulation of[unreadable] adiposity, feeding, and energy expenditure. The holoenzyme form of PKA interacts with cAMP to release[unreadable] active catalytic subunits that phosphorylate a variety of intracellular targets. This process is modulated by[unreadable] scaffolding proteins (AKAPs) and the expression of various isoforms of PKA with different biochemical[unreadable] properties. The goal of my laboratory is to develop mouse genetic approaches that can be used to study the[unreadable] role of PKA in physiological pathways that are not easily manipulated in cell culture models. Targeted[unreadable] disruption of the Rllbeta regulatory subunit gene of PKA creates mice that are lean and resistant to obesity and[unreadable] display a two-fold increase in nocturnal activity. These phenotypes have recently been traced to the brain[unreadable] and we propose to focus our efforts on determining the brain regions and specific cell types that are[unreadable] responsible. We also propose experiments to determine the changes in kinase activity that account for[unreadable] these phenotypes and the potential substrates that are involved. The application of mouse genetics to the[unreadable] study of body weight regulation has identified novel hormones, neural pathways, and intracellular signaling[unreadable] systems that have all proven to be applicable to humans. Our goal is to further understand the signaling[unreadable] interactions in the hope that this will lead to future therapeutic treatments for obesity.[unreadable] [unreadable]